title: Radiofrequency ablation suppresses distant tumour growth in a novel rat model of multifocal hepatocellular carcinoma.
abstract: RFA (radiofrequency ablation) is an established therapy for HCC (hepatocellular carcinoma). The multikinase inhibitor sorafenib prolongs survival in advanced HCC. We examined the effects of RFA alone and in combination with sorafenib on a bystanding tumour in a two-tumour rat model of HCC. A total of 80 rats were implanted with two liver tumours and randomized to four treatment groups: vehicle and sham operation (control), sorafenib and sham operation (Sora/Sham), vehicle and RFA (Vh/RFA), and sorafenib and RFA (Sora/RFA) (n=10/group per time point). RFA or sham-operation was performed on the left lobe tumour on day 15. Animals were killed at day 18 and day 30. Non-RFA-targeted right lobe tumours were analysed for angiogenesis, growth factors [HGF (hepatocyte growth factor), EGF (epidermal growth factor) and VEGF (vascular endothelial growth factor)] and infiltrating immune cells (CD3 and CD68). At day 30, the non-RFA-targeted tumours were significantly smaller in all three treatment groups compared with control (Sora/Sham P≤0.0001, Vh/RFA P=0.005 and Sora/RFA P≤0.0001). The smallest tumours were observed in animals treated with a combination of sorafenib and RFA, whereas the size reduction seen in the RFA-only group indicated an RFA-mediated distant suppression of tumour growth. Growth factor measurement revealed transiently decreased EGF levels after RFA (P=0.008), whereas sorafenib treatment decreased HGF levels (P=0.001). MVD (microvessel density) was reduced by sorafenib (P=0.002) despite increased VEGF levels (P≤0.0001). The immune parameters revealed augmented T-cells and IL-10 (interleukin 10) levels in all three treatment groups; sorafenib additionally increased macrophage numbers (P≤0.0001). RFA and sorafenib alone resulted in significant volume reduction of the non-RFA-targeted tumour; this effect was enhanced when both modalities were combined.
authors.affiliation: *Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Erös de Bethlenfalva-Hora
authors.forename: Joachim C
authors.initials: JC
authors.lastname: Mertens
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Piguet
authors.forename: Joachim
authors.initials: J
authors.lastname: Kettenbach
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmitt
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Weimann
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery*; D017115:Catheter Ablation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery*; D008264:Macrophages / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D000077157:Sorafenib; D013601:T-Lymphocytes / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D016212:Transforming Growth Factor beta; D042442:Vascular Endothelial Growth Factors; D016753:Interleukin-10; D009536:Niacinamide; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D000077157:Sorafenib